The Role of the Hyaluronan Receptor CD44 in MSC Migration in the Extracellular Matrix

¹ Comprehensive Transplant Center, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
² Cardiothoracic Surgery Research, The Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, California
³ Division of Research Immunology and Bone Marrow Transplantation, The Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, California

^* To whom correspondence should be addressed. E-mail: gordon.wu{at}cshs.org.

	Abstract

In previous investigation, we demonstrated that mesenchymal stem cells (MSC) actively migrated to cardiac allografts and contributed to graft fibrosis, and in less extent, to myocardial regeneration. The cellular/molecular mechanism responsible for MSC migration, however, is poorly understood. This paper examined the role of CD44-hyaluronan interaction in MSC migration, using a rat MSC line Ap8c3 and mouse CD44^-/- or CD44^+/+ bone marrow stromal cells (BMSC). PDGF stimulation of MSC Ap8c3 cells significantly increased the levels of cell surface CD44 detected by flow cytometry. The CD44 standard isoform was predominantly expressed by Ap8c3 cells, accounting for 90% of the CD44 mRNA determined by quantitative real time PCR. Mouse CD44^-/- BMSC bonded inefficiently to hyaluronic acid (HA) while CD44^+/+ BMSC and MSC Ap8c3 adhered strongly to HA. Adhesions of MSC Ap8c3 to HA were suppressed by anti-CD44 antibody, and by CD44 SiRNA. HA-coating of the migration chamber significantly promoted passage of CD44^+/+ BMSC or Ap8c3 cells but not CD44^-/- BMSC through the insert membranes (P<0.01). Migration of MSC Ap8c3 was significantly inhibited by anti-CD44 antibodies (P<0.01), and in less extent by CD44 SiRNA (P=0.05). The data indicate that MSC Ap8c3, in responses to PDGF stimulation express high levels of CD44 standard (CD44s) isoform, which facilitates cell migration through interaction with extracellular HA. Such migratory mechanism could be critical for recruitment of MSC into wound sites for the proposition of tissue regeneration, as well as for migration of fibroblast progenitors to allografts in the development of graft fibrosis.

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